Outcomes and Challenges of Hematopoietic Stem Cell Transplant in CD40L Deficiency

Introduction CD40 ligand (CD40L) deficiency is a rare X-linked primary immunodeficiency. Hematopoietic stem cell transplant (HSCT) is currently the only curative treatment. To date, regional studies have focused on reporting the clinical characteristics of this disease rather than transplant outcomes. This study aims to characterize pediatric patients with CD40L deficiency who have undergone HSCT in centers from Chile, Colombia, Brazil, Mexico, and Argentina. Objectives include describing clinical features, evaluating survival, identifying mortality-associated factors, and reporting major posttransplant complications. Methods We retrospectively reviewed pediatric patients with CD40L deficiency who underwent HSCT between January 2002 and December 2024. We analyzed clinical characteristics, survival outcomes, and complications. Descriptive statistics were used, and overall survival was estimated using Kaplan–Meier analysis. During this period, 27 patients with CD40L deficiency were included in the study. For one patient, data from a second HSCT were also collected. Results Twenty-seven pediatric patients with CD40L deficiency underwent HSCT, with a median age at transplant of 6 years (range 1–18). A confirmed genetic diagnosis was present in 96% of cases, and 12 patients (44%) had a positive family history. Pretransplant complications included pneumonia in 14 patients (52%), gastrointestinal symptoms in 15 patients (56%), neutropenia (26%), and cholangitis (11%). Infectious history included Pneumocystis jirovecii (22%), CMV (7%), Cryptosporidium (15%), and Candida (26%). Intravenous immunoglobulin (IVIG) supplementation was administered before transplant in 96% of patients, and 67% continued IVIG posttransplant. Cotrimoxazole prophylaxis was given prior to HSCT in 93% of cases. Unrelated donors were used in 70% of patients, and most received conditioning with treosulfan/busulfan plus fludarabine. Graft versus host disease (GVHD) prophylaxis included antithymocyte globulin (ATG) in 59% of patients and calcineurin inhibitors in 96%. Engraftment was achieved in 93% of patients, and 3 required a second transplant. Acute GVHD grade III–IV occurred in 30%, and chronic GVHD in 26%. CMV occurred in 10 patients, with one fatal case. A total of four deaths were reported—three were HSCT-related. Overall survival was 83.6% at 1 year, 78.7% at 3 years, and 78.7% at 5 years. Conclusions This multicenter retrospective study analyzed pediatric patients with CD40L deficiency who underwent HSCT. The cohort showed favorable 5-year overall survival. A genetic diagnosis was confirmed in 96% of patients, while one-third had a positive family history. Most patients experienced significant complications prior to transplant, and HSCT was delayed by a median of 5.5 years. Prophylaxis included IVIG in 96% of cases and cotrimoxazole in 93%. Most transplants used matched unrelated donors (MUD), with busulfan/fludarabine-based conditioning regimens. Conditioning approaches varied by center. Serotherapy (mainly ATG) was used in 70% of patients. Engraftment was successful in 93% of cases. Posttransplant complications were frequent. Acute GVHD occurred in 30% of patients, mostly in severe forms (grade III–IV), while 26% developed chronic GVHD. CMV reactivation was reported in 44%, and graft-related complications (“graft problems”), including secondary graft failure and mixed chimerism, were observed in 26% of cases.